WO2000063204A2 - Azoles substitues - Google Patents

Azoles substitues Download PDF

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Publication number
WO2000063204A2
WO2000063204A2 PCT/EP2000/003290 EP0003290W WO0063204A2 WO 2000063204 A2 WO2000063204 A2 WO 2000063204A2 EP 0003290 W EP0003290 W EP 0003290W WO 0063204 A2 WO0063204 A2 WO 0063204A2
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WIPO (PCT)
Prior art keywords
pyrimidyl
fluorophenyl
imidazole
amino
optionauy
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PCT/EP2000/003290
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German (de)
English (en)
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WO2000063204A3 (fr
Inventor
Lászlo Révész
Achim Schlapbach
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft M.B.H.
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Priority claimed from GBGB9908531.8A external-priority patent/GB9908531D0/en
Priority claimed from GBGB9908532.6A external-priority patent/GB9908532D0/en
Priority to MXPA01010434A priority Critical patent/MXPA01010434A/es
Priority to IL14583600A priority patent/IL145836A0/xx
Priority to BR0010598-8A priority patent/BR0010598A/pt
Priority to SK1456-2001A priority patent/SK14562001A3/sk
Priority to PL00364789A priority patent/PL364789A1/xx
Priority to JP2000612294A priority patent/JP2003503311A/ja
Priority to KR1020017013086A priority patent/KR20010108504A/ko
Priority to HU0302747A priority patent/HUP0302747A2/hu
Application filed by Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. filed Critical Novartis Ag
Priority to DE60003709T priority patent/DE60003709T2/de
Priority to AT00922630T priority patent/ATE244236T1/de
Priority to DK00922630T priority patent/DK1224180T3/da
Priority to SI200030185T priority patent/SI1224180T1/xx
Priority to CA002370417A priority patent/CA2370417A1/fr
Priority to EP00922630A priority patent/EP1224180B1/fr
Priority to AU42953/00A priority patent/AU4295300A/en
Publication of WO2000063204A2 publication Critical patent/WO2000063204A2/fr
Priority to NO20014987A priority patent/NO20014987L/no
Priority to US09/975,913 priority patent/US6579874B2/en
Publication of WO2000063204A3 publication Critical patent/WO2000063204A3/fr

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Definitions

  • This invention relates to substituted azoles and to their use for treating TNF ⁇ and EL-l mediated diseases such as rheumatoid arthritis and diseases of bone metabolism, e.g. osteoporosis.
  • a is N or C
  • b is CH when a is N, or O when a is C
  • Z is N or CH
  • W is -NR ⁇ -Y-, -O- or -S-, where Rs is H, C ⁇ -C 4 alkyl, C 3 -C 8 cycloalkyl, C 3 -CgcycloalkylC ⁇ . 3 alkyl, C 6 - Ci ⁇ aryl, C 3 -C ⁇ 8 heteroaryl, -C ⁇ aralkyl or C -C 19 heteroaralkyl, and -Y- is C alkylene or a direct bond ;
  • R 2 is phenyl, optionally substituted by one or more substituents, each of which is independently selected from halo, CF 3 , cyano, amido or thioamido, carboxylate or thiocarboxylate, C ⁇ -C 4 alkoxy, C ⁇ -C alkyl, or NH 2 which is optionally mono-or di-N-C C 4 alkyl substituted;
  • R 3 is H, halogen, C ⁇ -C ⁇ 0 alkyl, C C alkenyl, C 3 -C ⁇ ocycloalkyl, C 3 -C ⁇ 8 heterocycloalkyl, C 6 - Cisaryl, C 3 -Ci g heteroaryl, or methyleneaminoguanidinyl (i.e.
  • -CH N-NH-C(NH).NH 2 ), each of which is optionally substituted by up to 4 substituents separately selected from d- C alkyl optionally substituted by hydroxy, halogen, halo-substitued-C ⁇ -C 4 alkyl, hydroxy, C C alkoxy, C ⁇ -C alkylthio, carboxy, optionally C ⁇ -C 6 alkyl or Cr alkoxy substituted carbonyl, optionally mono-or di-N-Cj.-C alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom;
  • R 5 is Ce-Cigaryl, C 3 -C 18 heteroaryl, or C 3 -C 12 cycloalkyl each of which is optionally substituted by up to 4 substituents separately selected from C ⁇ -C 4 alkyl, halogen, halo- substitued-CrC alkyl, hydroxy, C C
  • halo or halogen denote I, Br, Cl or F.
  • the invention provides a 4-phenyl-5-[(2-substituted)-4-pyrimidyl or -pyridyl] -oxazole of formula I, or a pharmaceutically-acceptable and -cleavable ester thereof or acid addition salt thereof (wherein the numbering of the atoms of the oxazole ring is shown below in formula II.)
  • Z is N or CH
  • W is -NRe-Y-, -O- or -S-, where Re is H, C ⁇ -C 4 alkyl, C 3 -C 8 cycloalkyl, C3-C 8 cycloalkylCrC 3 alkyl, C 6 - Cisaryl, C 3 -Ci 8 heteroaryl, C 7 -C ⁇ 9 aralkyl or C -Ci9heteroaralkyl, and -Y- is C ⁇ -C alkylene or a direct bond ;
  • R ⁇ 2 is phenyl, optionally substituted by one or more substituents, each of which is independently selected from halo, CF 3 .
  • R 13 is H, halogen, C ⁇ -C ⁇ 0 alkyl, d-C 4 alkenyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C ⁇ 8 heterocycloalkyl, C 6 - Ci 8 aryl, C 3 -Ci 8 heteroaryl, or methyleneaminoguanidinyl (i.e.
  • -CH N-NH-C(NH).NH 2 ), each of which is optionally substituted by up to 4 substituents separately selected from d- C 4 alkyl optionally substituted by hydroxy, halogen, halo-substitued-C alkyl, hydroxy, Ci- 4 alkoxy, C alkylthio, carboxy, optionally C C 6 alkyl or d-C 6 alkoxy substituted carbonyl, optionally mono-or di-N-C alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom; Ri 5 is C 6 -C ⁇ 8 aryl, C 3 -C ⁇ 8 heteroaryl, or C 3 -C 12 cycloalkyl each of which is optionally substituted by up to 4 substituents separately selected from Ci- alkyl, halogen, halo- substitued-C ⁇ -C 4 alkyl, hydroxy, C ⁇ -C 4 al
  • R 13 is heteroaryl it is preferably pyridyl (e.g. 4-pyridyl) or pyrimidyl, each optionally substituted, e.g. by up to 2 substituents, separately selected from C ⁇ -C 4 alkyl optionally substituted by hydroxy, halogen, hydroxy, C)-C alkoxy, carboxy, optionally C ⁇ -C 6 alkyl or C ⁇ -C 6 alkoxy substituted carbonyl, or optionally mono-or di-N-d-C 4 alkyl substituted amino.
  • pyridyl e.g. 4-pyridyl
  • pyrimidyl each optionally substituted, e.g. by up to 2 substituents, separately selected from C ⁇ -C 4 alkyl optionally substituted by hydroxy, halogen, hydroxy, C)-C alkoxy, carboxy, optionally C ⁇ -C 6 alkyl or C ⁇ -C 6 alkoxy substituted carbonyl, or optionally mono-or di-
  • R 13 is cycloalkyl it is preferably C 3 -C 8 , especially C 5 -C 6 cycloalkyl (e.g. cyclohexyl), optionally substituted, e.g. by 1 or 2 substituents, separately selected from C ⁇ -C alkyl, halogen, hydroxy, C ⁇ -C 4 alkoxy, or optionally mono-or di-N-C ⁇ -C alkyl substituted amino.
  • C 3 -C 8 especially C 5 -C 6 cycloalkyl (e.g. cyclohexyl), optionally substituted, e.g. by 1 or 2 substituents, separately selected from C ⁇ -C alkyl, halogen, hydroxy, C ⁇ -C 4 alkoxy, or optionally mono-or di-N-C ⁇ -C alkyl substituted amino.
  • R ⁇ is heterocycloalkyl it is preferably N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, e.g. N or O, and is optionally substituted, e.g. by 1 or 2 substituents, separately selected from C ⁇ -C alkyl optionally substituted by hydroxy, halogen, hydroxy, C C alkoxy, carboxy, optionally d-Qalkyl or d-Qalkoxy substituted carbonyl, or optionally mono-or substituted amino.
  • R 15 is aryl it is preferably phenyl.
  • R ⁇ 5 is cycloalkyl, it is preferably C 3 -C 7 cycloalkyl, e.g.
  • R ⁇ 5 may be unsubstituted or substituted, conveniently mono-substituted, e.g. phenyl conveniently meta or para substituted, by halogen, Ci-Cinalkyl, halo-substitued d-Cioalkyl, C C 10 alkoxy, hydroxy or -NR 7 R 3 , where R 7 and Re are idependently H, Ci-C ⁇ alkyl, C ⁇ -Cioaryl, C 6 -C 10 heteroaryl, C 7 -C ⁇ aralkyl or C 7 - Cnheteroaralkyl.
  • Y is C ⁇ -C alkylene, it is preferably d-C 2 alkylene, and is optionally substituted, e.g. by C ⁇ -C 4 alkyl (e.g. methyl), halogen, hydroxy, C ⁇ -C 4 alkoxy, or amino.
  • C ⁇ -C 4 alkyl e.g. methyl
  • halogen hydroxy, C ⁇ -C 4 alkoxy, or amino.
  • R ⁇ 2 is phenyl substituted, preferably mono- or di-substituted, by halogen or a halogen-containing group, e.g. 4-fluorophen-l-yl, or 3-CF 3 , 3-C1, or 3,4-difluoro substituted.
  • halogen e.g. 4-fluorophen-l-yl, or 3-CF 3 , 3-C1, or 3,4-difluoro substituted.
  • R ⁇ 3 is H, C C 4 alkenyl, phenyl, pyridyl, morpholinyl, piperidinyl, piperazinyl, or N-mono- or each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from d-C alkyl optionally substituted by hydroxy, halogen, hydroxy, C ⁇ -C alkoxy, carboxy, optionally C ⁇ -C 6 alkyl or C ⁇ -C 6 alkoxy substituted carbonyl, or optionally mono-or di-N-C ⁇ -C 4 alkyl substituted amino.
  • W is -NH-Y'-, -O- or -S-, where Y' is -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )- or a direct bond
  • R 15 ' is phenyl or C3-C 7 cycloalkyl each of which is optionally mono-substituted by halogen, Ci-doalkyl, Ci-Cioalkoxy, hydroxy, trihalomethyl or -NR 7 Rg, where R 7 and R 8 are idependently H, d-C 6 alkyl, CVCioaryl. C 6 -C ⁇ 0 heteroaryl, C 7 -C ⁇ aralkyl or C 7 - C ⁇ heteroaralkyl;
  • R 10 is halogen, CF 3 , cyano, amido, thioamido, amino
  • R 13 ' is H, Ci-C ⁇ alkyl, C ⁇ -C alkenyl, phenyl, pyridyl, morpholinyl, piperidinyl, piperazinyl, or N-mono- or di-C ⁇ -C 4 alkylamino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C ⁇ -C alkyl optionally substituted by hydroxy, halogen, hydroxy, d-C alkoxy, carboxy, optionally d-C ⁇ alkyl or d-C ⁇ alkoxy substituted carbonyl, or optionally mono-or di-N-C ⁇ -C alkyl substituted amino;
  • Z is N or CH and
  • W' is -NH-Y'-, -O- or -S-, where Y' is -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )- or a direct bond, and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof .
  • R 15 ' is unsubstituted or monosubstituted by halogen, d ⁇ a-kyl (e.g. methyl), Ci- alkoxy (e.g. methoxy), hydroxy or CF 3 .
  • Rio is halogen, e.g. F, or CF 3 .
  • R ⁇ 3 ' is Crdalkyl, morpholinyl, piperidinyl, piperazinyl, or N-mono- or di-Ci- C 4 alkylamino, each of which is optionally substituted, e.g. by up to 2 substituents, separately selected from C ⁇ -C alkyl optionally substituted by hydroxy, carboxy, optionally C ⁇ -C 6 alkyl or d- dalkoxy substituted carbonyl, or amino.
  • W is -NH-Y"- where -Y"- is -CH 2 -, -CH(CH 3 )- or a direct bond.
  • the Invention includes the following compounds of formula II:
  • the invention provides a l-[(2-substituted)-4-pyrimidyl]-2- phenyl-imidazole of formula I or a pharmaceutically-acceptable and -cleavable ester thereof or acid addition salt thereof. (The numbering of the atoms of the imidazole ring is shown below in formula HI.)
  • R* is H, C C 4 alkyl, d-C ⁇ cycloalkyl, d-CscycloalkylC.-dalkyl, C 6 - Ci ⁇ aryl, C3-C ⁇ 8 heteroaryl, C 7 -Ci 9 aralkyl or C 4 -d 9 heteroaralkyl, and -Y- is C ⁇ -C alkylene or a direct bond ;
  • R 22 is phenyl, optionally substituted by one or more substituents, each of which is independently selected from halo, CF 3 , cyano, amido or thioamido, carboxylate or thiocarboxylate, C ⁇ -C alkoxy, C ⁇ -C alkyl, or NH 2 which is optionally mono-or di-N-C ⁇ -C 4 alkyl substituted;
  • R 23 is H, halogen, d-Cioalkyl, C ⁇ -C 4 alkenyl, C 3 -C 10 cycloalkyl
  • -CH N-NH-C(NH)NH 2 ), each of which may be optionally substituted by up to 4 substituents separately selected from d- C alkyl optionally substituted by hydroxy, halogen, halo-substitued-Ci ⁇ alkyl, hydroxy, Ci- 4 alkoxy, carboxy, optionally C ⁇ -C 6 alkyl or d-C 6 alkoxy substituted carbonyl, optionally mono-or di-N-C ⁇ alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom;
  • R 25 is C ⁇ -Cigaryl, C 3 -C ⁇ 8 heteroaryl, or C 3 -C ⁇ 2 cycloalkyl each of which is optionally substituted by up to 4 substituents separately selected from d-Qalkyl, halogen, halo- substitued-C ⁇ -C alkyl, hydroxy, C ⁇ -C 4 alkoxy, C ⁇ -C alkylthio, or optionally mono-or di-N- C ⁇ -C 4 alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof .
  • R 23 is aryl, it is preferably phenyl optionally substituted, e.g. by up to 2 substituents, separately selected from Ci-Qalkyl optionally substituted by hydroxy, halogen, hydroxy, Q- C 4 alkoxy, carboxy, optionally Ci-Qalkyl or Q-Qalkoxy substituted carbonyl, optionally mono-or di-N-C ⁇ -C alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom.
  • Ci-Qalkyl optionally substituted by hydroxy, halogen, hydroxy, Q- C 4 alkoxy, carboxy, optionally Ci-Qalkyl or Q-Qalkoxy substituted carbonyl, optionally mono-or di-N-C ⁇ -C alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom.
  • R 23 is heteroaryl it is preferably pyridyl (e.g. 4-pyridyl or 3-pyridyl), pyrimidyl, thienyl, furyl, or benzofuryl, each optionally substituted, e.g. by up to 2 substituents, separately selected from d-C alkyl optionally substituted by hydroxy, halogen, hydroxy, C ⁇ -C alkoxy, carboxy, optionally C ⁇ -C 6 alkyl or Q-Qalkoxy substituted carbonyl, optionally mono-or di-N-Q- C 4 alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom.
  • pyridyl e.g. 4-pyridyl or 3-pyridyl
  • pyrimidyl e.g. 4-pyridyl or 3-pyridyl
  • thienyl thienyl
  • R 23 is cycloalkyl it is preferably C 3 -C 8 , especially Q-Qcycloalkyl (e.g. cyclohexyl), optionally substituted, e.g. by 1 or 2 substituents, separately selected from Q ⁇ alkyl, halogen, hydroxy, C alkoxy, or optionally mono-or substituted amino.
  • Q-Qcycloalkyl e.g. cyclohexyl
  • R 23 is heterocycloalkyl it is preferably N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, e.g. N or O, and is optionally substituted , e.g.
  • substituents separately selected from d-Qalkyl optionally substituted by hydroxy, halogen, hydroxy, Q-Qalkoxy, carboxy, optionally Ci-Qalkyl or Q-Qalkoxy substituted carbonyl, optionally mono-or di-N-Q-Qalkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom.
  • R 25 When R 25 is aryl it is preferably phenyl. When R 25 is cycloalkyl, it is preferably Q-Q cycloalkyl, e.g. cylopropyl, cyclopentyl, cyclohexyl or cycloheptyl. R 25 may be unsubstituted or substituted, conveniently mono-substituted, e.g.
  • phenyl conveniently meta or para substituted, by halogen, Q-Qoalkyl, halo-substitued Q-Qoalkyl, Q-Q 0 alkoxy, hydroxy or -NR 7 Rg, where R 7 and R 8 are idependently H, Q-Qalkyl, Q-Qoaryl, Q-Qoheteroaryl, Q-Qiaralkyl or Q- C ⁇ heteroar alkyl.
  • Y is Q-Q alkylene, it is preferably Q-Q alkylene, and is optionally substituted, e.g. by Q-Qalkyl (e.g. methyl), halogen, hydroxy, alkoxy, or amino.
  • Q-Qalkyl e.g. methyl
  • halogen hydroxy, alkoxy, or amino.
  • R 22 is phenyl substituted, preferably mono- or disubstituted, by halogen or a halogen-contairiing group, e.g. 4-fluorophen-l-yl, or 3-CF 3 , 3-C1, or 3,4-difluoro substituted phenyl.
  • halogen or a halogen-contairiing group e.g. 4-fluorophen-l-yl, or 3-CF 3 , 3-C1, or 3,4-difluoro substituted phenyl.
  • R 23 is H, halogen, Q-ealkyl, vinyl, phenyl, pyridyl, pyrimidyl, benzofuryl, furyl, thienyl, morpholinyl, piperidinyl, nortropanyl, piperazinyl, methyleneaminoguanidinyl or N- mono- or di-Q-Qalkylamino, each of which is optionally substituted, e.g.
  • substituents separately selected from Q-Qalkyl optionally substitued by, halogen, hydroxy, Q-Qalkoxy, carboxy, optionally Q-Qalkyl or Q-Qalkoxy substituted carbonyl, optionally mono-or di-N-Q- Qalkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom.
  • X is -NH-Y'-, -O- or -S-, where Y' is -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )- or a direct bond.
  • X is -NH-CH(CH 3 )-.
  • R' 25 is phenyl or Q-Qcycloalkyl each of which is optionally mono-substituted by halogen, Q-Qoalkyl, Q-Qoalkoxy, hydroxy, trihalomethyl or -NR 7 Rs, where R 7 and Rs are idependently H, Q-Qalkyl, Q-Qoaryl, Q-Q 0 heteroaryl, Q-Qiaralkyl or Q- Qiheteroar alkyl;
  • Rio is halogen, CF3, cyano, amido, thioamido, amino or Q-Qalkyl
  • R' 23 is H, halogen, C ⁇ -C 6 alkyl, vinyl, phenyl, pyridyl, pyrimidyl, benzofuryl, furyl, thienyl, morpholinyl, piperidinyl, nortropanyl, piperazinyl, methyleneaminoguanidinyl or N-mono- or di-Q-Qalkylamino, each of which is optionally substituted, e.g.
  • substituents separately selected from Q-Qalkyl optionally substitued by hydroxy, halogen, hydroxy, Q- Qalkoxy, carboxy, optionally Q-Qalkyl or Q-Qalkoxy substituted carbonyl, optionally mono-or di-N-Q-Qalkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom, and W' is -NH-Y'-, -O- or -S-, where Y' is -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )- or a direct bond, and pharmaceutically-acceptable and -cleavable esters thereof and acid addition salts thereof .
  • R' 25 is unsubstituted or monosubstituted by halogen, Q ⁇ alkyl (e.g. methyl), Q. alkoxy (e.g. methoxy), hydroxy or CF 3 .
  • R'23 is halogen, vinyl, phenyl, pyridyl, pyrimidyl, benzofuryl, furyl, thienyl, piperidinyl, nortropanyl, or methyleneaminoguanidinyl, each of which is optionally substituted, e.g.
  • substituents separately selected from Q-Qalkyl optionally substuted by hydroxy, halogen, hydroxy, Q-Qalkoxy, carboxy, optionally Q-Qalkyl or Q-Qalkoxy substituted carbonyl, optionally mono-or di-N-Q-Qalkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom
  • R ⁇ 0 is halogen, e.g. F, or CF 3 .
  • ' is -NH-Y'" where Y'" is -CH(CH 3 )- or a direct bond.
  • the Invention includes the following compounds of formula IH:
  • the compounds of formulae ⁇ and III contain at least 1 assymetric carbon atom within this alkylene moiety.
  • the resulting diastereoisomers and enantiomers are encompassed by the instant invention.
  • the compounds of formulae n and in are provided in pure or substantially pure epimeric form, e.g. as compositions in which the compounds are present in a form comprising at least 90%, e.g. preferably at least 95% of a single epimer (i.e. comprising less than 10%, e.g. preferably less than 5% of other epimeric forms).
  • Preferred epimeric compounds of formulae II and HI are described hereinafter in the Examples.
  • heteroaryl denote heteroaryl, heteroaralkyl or heterocycloalkyl substituents comprising at least 3 ring atoms, at least one of which is a hetero atom, e.g.N, O or S, and which in the case of Q-Q 9 heteroaralkyl groups are attached via an alkylene moiety comprising at least 1 carbon atom.
  • heteroaryl includes unsaturated cyclic moieties containing heteroatoms, including furyl, benzofuryl, thienyl and the like.
  • novel oxazoles and imidazoles of the invention in particular the compounds of formulae ⁇ , IT, in and HI' and the specific compounds listed above are hereinafter referred to "Agents of the Invention".
  • the Agents of the Invention which comprise free hydroxyl groups may also exist in the form of esters, e.g. pharmaceutically acceptable, physiologically cleavable esters, and as such are included within the scope of the invention.
  • Such pharmaceutically acceptable esters are preferably prodrug ester derivatives, such being convertible by solvolysis or cleavage under physiological conditions to the corresponding Agents of the Invention which comprise free hydroxyl groups.
  • Suitable pharmaceutically acceptable prodrug esters are those derived from a carboxylic acid, a carbonic acid monoester or a carbamic acid, advantageously esters derived from an optionally substituted lower alkanoic acid or an arylcarboxylic acid.
  • Agents of the Invention may also exist in the form of salts, e.g. pharmaceutically acceptable salts, and as such are included within the scope of the invention.
  • Pharmaceutically acceptable salts include acid addition salts with conventional acids, for example, mineral acids, e.g., hydrochloric acid, sulfiiric or phosphoric acid, or organic acids, for example, aliphatic or aromatic carboxylic or sulfonic acids, e.g., acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, hydroxymaleic, pyruvic, pamoic, methanesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; also amino acids, such as arginine and lysine.
  • pharmaceutically acceptable salts also represent metal or ammonium salts, such as alkali metal or alkaline earth metal salts, e.g., sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are formed with ammonia or suitable organic amines.
  • metal or ammonium salts such as alkali metal or alkaline earth metal salts, e.g., sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are formed with ammonia or suitable organic amines.
  • R' ⁇ 3 , R' ⁇ 5 , Rio and Z are as previously defined and W" is -NH-, may be prepared by reacting the corresponding precursor compound of formula IN or IN'
  • R' ⁇ 3 and Rio are as previously defined, with the corresponding R' ⁇ 5 -NH 2 derivative.
  • the reaction may be carried out by refluxing the reactants in an organic solvent, e.g. dichloroethane, e.g. in the presence of diethoxytrifluoroborane. Thereafter, if desired, the compound of Formula H" obtained may be converted into a further compound of Formula ⁇ " or otherwise treated as required.
  • the precursor compound of formula IN may be prepared by controlled oxidation of the corresponding 5(2-methyltWo-4-pyrimidyl)-4-phenylimidazole, e.g. employing an oxidising agent such as mCPBA (meta chloroperbenzoic acid), conveniently in an organic solvent such as methylene chloride.
  • mCPBA metal chloroperbenzoic acid
  • the corresponding 5(-4-pyrimidyl/pyridyl)-4-phenyloxazole compound may be prepared by contacting the corresponding acetophenone precursor compound of formula N or V
  • the compounds of formula V and V may be prepared by bromination of the corresponding acetophenone, e.g. 2-(2-methylthio-4-pyrimidyl)acetophenone.
  • the acetophenone precursor may be prepared by reacting the corresponding N-methoxy-N- methylbenzamide with the corresponding pyrimidine, e.g. 4-methyl-2-(methylthio) pyrimidine, for instance in a THF containing organic solvent with cooling.
  • the invention includes a process for the preparation of a compound of formula H" wherein R' ⁇ 3 , R' 15 , Rio and Z are as previously defined and W" is -NH-, which comprises reacting the corresponding precursor compound of formula IN or IN'
  • R' 13 , Rio and Z are as previously defined, with the corresponding R' ⁇ 5 - ⁇ H 2 amine, and thereafter, if desired, converting the compound of formula H" obtained into a further compound of formula H" or a pharmaceuticallyracceptable and -cleavable ester thereof or acid addition salt thereof.
  • R'23, R'25 and Rio are as previously defined and W" is -NH- or -O-, may be prepared by reacting the corresponding compound of formula I" in which R'2 3 is halogen, e.g. Br, with the corresponding R' 23 ketone or activated R'23 precursor, e.g. tri-alkylstannyl activated R' 23 precursor.
  • the reaction may be carried out, e.g. in the presence of a reducing agent, such as BuLi or PdCl 2 (PPh 3 ) 2 , by refluxing the reactants, and/or with cooling, in an organic solvent, as appropriate.
  • a reducing agent such as BuLi or PdCl 2 (PPh 3 ) 2
  • the compound of formula m" in which R' 23 is halogen, e.g. Br, may be prepared reacting the corresponding precursor compound of formula NI
  • the reaction may be carried out by refluxing the reactants in an organic solvent, e.g. dichloroethane, e.g. in the presence of diethoxytrifluoroborane.
  • organic solvent e.g. dichloroethane, e.g. in the presence of diethoxytrifluoroborane.
  • the corresponding l(2-methyltWo-4-pyrimidyl)-2-phenyl-4-bromo-imidazole compound may be prepared by reacting the corresponding 2-phenyl-4-bromo-imidazole compound with 4- chloro-2-methylthiopyrimidine, e.g. in the presence of KN(TMS) 2 in an organic solvent sucgh as DMF.
  • the 2-phenyl-4-bromo-imidazole compound may be obtained by removal of the trimethylsilanyl-ethoxymethyl from the corresponding l-trimethylsilanyl-ethoxymethyl-2-phenyl- 4-bromo-imidazole compound, which in turn may be prepared from 4,5-dibromo compound, whichin turn may be prepared by phenylation of the known compound, 2,4,5-tribromo-l-(2- trimethylsilanyl-ethoxymethyl)imidazole (Tetrahedron Letters (1998), 39(29),5171-5174); for instance as hereinafter described in the Examples.
  • the invention includes a process for the preparation of a compound of formula DI" wherein R' 23 , R' 2 s and Rio are as previously defined and W" is -NH- or -O-, comprising reacting a corresponding compound of formula ⁇ i" in which R' 23 is halogen, e.g. Br, with the corresponding R'23 ketone or activated R' 23 precursor, e.g. tri-alkylstannyl activated R' 23 precursor, and thereafter, if desired, converting the compound of formula I" obtained into a further compound of formula HI" or a pharmaceutically-acceptable and -cleavable ester thereof or acid addition salt thereof.
  • halogen e.g. Br
  • R' 23 precursor e.g. tri-alkylstannyl activated R' 23 precursor
  • Example 1 4-(4-Fluorophenyl -5-(2-ri-(S)-phenylethyl1amino-4-Dyrimidyl)-2-N- morpholinyloxazole a 4-Fluoro-2-(2-methylthio-4-pyrimidvI acetophenone
  • n-BuLi (10 ml of a 1.6 M solution in hexane; 12 mmol) is added at -78°C to a solution of diisopropylamine (2.48 ml; 17 mmol) in THF (15 ml) and stirred for 5 min.
  • 4-Methyl-2- (methylthio)pyrimidine (2g; 14.5 mmol) dissolved in THF (2 ml) is added dropwise and stirred for 30 min at -78 C.
  • 4-Fluoro-N-methoxy-N-methylbenzamide (2.66 g; 14.5 mmol) is dissolved in THF (3 ml) and added slowly to the reaction mixture. The mixture is warmed to r.t. within 45 min.
  • Example 2 4-(4-Fluorophenyl)-5-(2-ri-(S)-phenylethyl1amino-4-pyrimidylV2-N- piperidinyloxazole a 4-(4-Fluorophenyl)-5-(r2-methylthio1-4-pyrimidvI)-2-N-piperidinvIoxazole
  • Example 8 4-(4-Fluorophenvn-5-(2-ri-(S)-phenylethyllamino-4-pyrimidvn-2-(4-NH- piperidine-l-yl)oxazole
  • Example 9 4-(4-Fluorophenyl ' )-5-(2-cvclopropylmethylamino-4-pyrimidyl)-2-(4-NH- piperidin-1-yr.oxazole
  • ExamplelO 4-(4-Fluorophenyl)-5-(2-ri-(S)-phenylethvnamino-4-pyrimldyl)-2-(4-N-acetvI- pjperidine- 1 -vDoxazole
  • Example 12 4-(4-FIuorophenvn-5-(2-ri-(S)-phenylethvnamino-4-pyrimidvn-2-(l- piperazinyl) oxazole
  • aqueous phase is extracted three times with ethyl acetate.
  • the combined organic phases are washed with water, dried over Na 2 SO , filtered and evaporated to dryness to give a foam, which was purified by SiO 2 chromatography (TBME/MeOH/NH 3 cone 90/9/1 to 85/15/1.5) to yield the title compound as a yeUow foam (80 mg; 72 %).
  • Example 13 4-(4-FluorophenvI)-5-(2-ri-(S)-phenylethvnamino-4-pyrimidvD-2-(l-amino-l- methvDethyloxazole a) 4-(4-Fluorophenyl)-5-(2-methylthio-4-pyrimidyl)-2-(l-N-benzyloxy-carbonyl)amino-l- methvDethyloxazole
  • reaction mixture is evaporated and purified via SiO 2 chromatography (acetone/cyclohexane
  • Example 14 4-(4-Fluorophenyl -5-(2-ri-(S -phenylethyl1amino-4-pyrimidyl)-2-(l-hydroxy-
  • Example 15 4-(4-FIuorophenyl)-2-(l-hvdroxy-4-methyl)piperidine-l-yl)-5-(2-fcvclopropyl- methvnamino-4-pyridyl)oxazole a) 4-(4-Fluorophenyl)-2-(l-hvdroxy-4-methyl)piperidine-l-yl)-5-(2-fluoro-4-pyridyl)oxazole
  • Example 16 4-(4-Fluorophenyl -2-(l-hydroxy-4-ethyl)piperidine-l-yl)-5-(2-cvcIohexyI amino-4-pyridyl)oxazole
  • the title compound is prepared according to the procedure above and obtained as cream colored crystals in 48% yield.
  • Example 18 4-(4-FluorophenvD-2-(4-NH-piperidine-l-yl)-5-(2-(l-(S)-phenylethvna ⁇ nino-4- pyridvDoxazole a 4-(4-Fluorophenyl)-2-(4-N-tert.butylo ⁇ y carbonyl)piperidine-l-yl -5-(2-fluoro-4- pyridvDoxazole
  • the aqueous phase is adjusted to pH -10 by adding a saturated solution of Na 2 CO3 and extracted with ethyl acetate three times.
  • the combined organic phases are washed with water, dried over Na 2 SO 4 , filtered and evaporated to dryness and yielded the piperidine NH analogue of the title compound (177 mg; 0.52 mmol; 8%), which is treated with (BOQ 2 O (150 mg; 0.68 mmol) in THF (2 ml) for lh at room temperature.
  • the reaction mixture is evaporated to yield the title compound as a colorless foam (270 mg), which is directly used for the next step without purification.
  • Example 19 4-(4-Fluorophenyl)-2-(4-NH-piperidine-l-yl)-5-(2-cvclopropylmethylamino-4- pyridvDoxazole a) 4-(4-Fluorophenyl)-2-(4-N-tert.butyloxy carbonyl)piperidine-l-yl)-5-(2- cvclopropyImethyl amino-4-pyridyl)oxazole
  • Example 20 4-(4-Fluorophenyl)-2-(4-N-(2-hvdroxy-2-methyl)propylpiperidine-l-yl)-5-(2- cvclopropylmethylamino-4-pyridyl)oxazole
  • Example 21 4-(4-Fluorophenyl)-2-(4-NH-piperidine-l-yl)-5-(2-cvclohexylaPMno-4- pyridvDoxazole at 4-(4-Fluoro p henyl ) -2- ( 4-N-tert.butylo ⁇ y carbonyl)piperidine-l-yl -5-(2- cvclohexyl amino-4-pyridyl)oxazole
  • Example 23 4-(4-FIuorophenyl)-2-(4-N-(2-hvdroxy-2-methyl)propylpiperidine-l-yl)-5-(2- cvclohe ⁇ ylamino-4-pyridyl)oxazole
  • the title compound is prepared according to the procedure above and obtained as colorless crystals in 95% yield.
  • the title compound is prepared according to the procedure above and obtained as colorless crystals in 95% yield.
  • Example 25 4-(4-Fluorophenyl)-2-(4-N-(2-hvdro ⁇ y-2-methyl)propylpiperidine-l-yl)-5-(2- (l-(S)-phenylethyl)amino-4-pyrimidvI oxazole
  • 4,5-Dibromo-2-(4-fluorophenyl)-l-(2-trimethylsUanyl-ethoxymethyl)imidazole (10.8 g; 25 mmol) are dissolved in THF (108 ml) and cooled to -78C under argon. N-BuLi (15.6 ml; 1.6 M) is added under stirring within 15 min. After 30 min at -78 C, isopropanol (7.8 ml; 0.1 mol) is introduced dropwise and the mixture warmed to room temperature. Water is added to the reaction mixture and the aqueous phase extracted three times with ethyl acetate.
  • the title compound is prepared according to the procedure described above and obtained as colorless crystals in 76% yield.
  • the title compound is prepared according to the procedure above, obtained as a viscuous oU in quantitative yield and used in the next step without further purification.
  • the title compound is prepared according to the procedure described above and obtained as sUghtly yeUow crystals in 61.3% yield.
  • the title compound is prepared according to the procedure described above and obtained as sUghtly yeUow crystals in 90% yield.
  • the title compound is prepared according to the procedure described above and obtained as sUghtly yeUow crystals in 78% yield.
  • the title compound is prepared according to the procedure described above and obtained as sUghtly yeUow crystals in 73% yield.
  • Example 30 2-(4-Fluorophenyl)-4-(l-methyl-4-hvdro ⁇ ypiperidin-4-yl)-l-(2-fl-(S)-phenyl- ethyll amino-4-p yrimidvDimidazole
  • the title compound is prepared according to the procedure described above and obtained as sUghtly yeUow crystals in 46% yield.
  • the title compound is prepared according to the procedure described above (THF/isopentane mixture was used as solvent and nBuLi was added at -100°C) and obtained as colorless viscuous oU in 42% yield. Crystallisation as fumarate salt was performed from acetone providing colorless crystals with m.p. 189-193°C.
  • reaction mixture After filtration and evaporation, the reaction mixture is purified by preparative HPLC on LiChrospher RP-18 (GUson HPLC-system; column tube: 125 mm x 25 mm ID) with MeCN/water as elution system, 40:60 to 100:0 as gradient and a flow rate of 10 rnl/min. to yield the title product as white foam (35 mg; 36%).
  • Example 40 The compounds of Examples 36 to 39 and the precursor a) of Example 40 are simUarly prepared by coupling 4-Bromo-2-(4-fluorophenyl)-l-(2-[l-(S)-phenylethyl]amino-4- pyrimidyl)i-midazole with heteroarylstannanes as described above:
  • Example 37 2-(4-Fluorophenyl -l-(2-ri-(S)-phenyl-ethyllamino-4-pyrimidyl) 4-(3-pyridvD- imidazole
  • Example 38 2-(4-Fluorophenyl -l-(2-ri-(S)-phenyl-ethyllamino-4-pyrimidvI) 4-(2-thienyl - imidazole
  • Example 40 2-(4-Fluorophenyl)-l-(2-ri-(S)-phenyl-ethvnamino-4-pyrimidv 4-(2- amino)pyrimidylimidazole a) 2-(4-Fluorophenyl -l-(2 1-(S)-phenyl-ethyllamino-4-pyrimidyl) 4-(2-methylthio) pyrimidylimidazole
  • reaction mixture is heated to 80 C for 3h and gives after evaporation of the solvent and purification by preparative HPLC on LiChrospher RP-18 (Gilson HPLC-system; column tube: 125 mm x 25 mm ID) with MeCN/water as elution system, 40:60 to 100:0 as gradient and a flow rate of 10 ml/min the title product as colorless crystals (13 mg; 31%).
  • Example 41 2-(4-Fluorophenyl)-l-(2-ri-(S -phenyl-ethyl1amino-4-pyrimidyl) 4-(2- hvdroxy)pyrimidylimidazole
  • the sulfoxide (50 mg; 0.1 mmol) is dissolved in dioxan/water (5 ml 5/1) and tretaed with 3 N KOH (0.1 ml) for 1 h at room temperature.
  • the reaction mixture is acidified with 2 N HC1 and extracted twice with ethyl acetate.
  • reaction mixture is evaporated to dryness and purified by preparative HPLC on LiChrospher RP-18 (Gilson HPLC-system; column tube: 125 mm x 25 mm ID) with MeCN/water as elution system, 40:60 to 100:0 as gradient and a flow rate of 10 ml/min to yield the title product as colorless crystals (25 mg; 48%).
  • Example 43 2- ( 4-Fluorophenyl ) -l- ( 2-n- ( S ) -phenyl-ethvnamino-4-pyrimidvn-4-(3-thienyl)- imidazole
  • Example 49 2-(4--- ⁇ uorophenyI)-l-(2-[l-(S)-phenyl-ethyl]amino-4-pyrin ⁇ idyl)-4-(3-chloro phenyl)imidazole (AAL395)
  • Example 50 2-(4-Fluorophenyl)-l-(2-ri-(S)-phenyl-ethvnamino-4-pyrimidylV4- methyleneaminoguanidinyl-imidazole a) 2-(4-Fluorophenyl)-l-(2-ri-(S)-phenyl-ethvnamino-4-pyrimidyl)-4-(3-formyl)- imidazole
  • 2-(4-Huorophenyl)-l-(2-[l-(S)-phenylethyl]ammo-4-pyrinMdyl)-4-(3-formyl)imidazole (26 mg; 0.068 mmol) is dissolved in EtOH (0.5 ml) and 5.5 N HC1 in isopropanol (0.5 ml) and treated with aminoguanidine-hydrogencarbonate (18.5 mg; 0.13 mmol).
  • the reaction mixture is dUuted with MeOH (1.5 ml) and left at room temperature over night and is poured on saturated Na 2 CO 3 solution and extracted with ethyl acetate three times.
  • Example 51 2-(4-Fluorophenyl)-l-(2-(l-(S -phenylethyl)amino-4-pyrimidyl)-4-(4- ethoxycarbonyl)piperidine-l-yl imidazole a) 4-(4-EthoxycarbonvI-l-hvdro ⁇ ypiperidine-l-yl)-2-(4-fluorophenyl -l-(2-(trimethylsiIyl) ethoxymethylimidazole
  • nBuLi (8.25 ml of a 1.6 M solution in hexane; 13.2 mmol) is added under argon within 10 min to a precooled and stirred solution (-78 C) of 4-bromo-2-(4-fluorophenyl)-l-(2-(trimethylsUyl) ethoxy-methyl)imidazole (4.45 g; 12 mmol) in THF (50 ml). Stirring is continued for 15 min at - 78 C. N-Ethoxycarbonyl-4-piperidone (2.35 ml; 15.6 mmol) is introduced within 2 min.
  • Example 55 2-(4-Fluorophenyl)-l-(2-cvclopentvI)amino-4-pyrimidyl)-4-(4-(2-hvdroxy-2- methvDpropylpiperidine- 1 - yl imidazole
  • the title compound is prepared according to the procedures described above and is obtained as colorless crystals in 73% yield.
  • Example 56 2-(4-Fluorophenyl)-l-(2-(l-(S)-phenylethyl)amino-4-pyrimidyl -4-(4-methyl)- piperidine-1-yl imidazole
  • Example 58 2-(4-Fluorophenyl)-l-(2-(l-(S)-phenylethvnamino-4-pyrimidvI -4-(l- hvdro ⁇ y)piperidine-l-yl imidazole
  • Example 59 2-(4-Fluorophenyl)-l-(2-(l-(S)-phenylethyl)amino-4-pyrimidyl -4-(3a- hvdroxy-N-tert.butyloxycarbonylnortropan-3b-yl) imidazole
  • Example 60 2-(4-Fluorophenyl -l-(2-(l-(S)-phenylethyl amino-4-pyrimidvI -4-(3a- hvdroxy-nortropan-3b-vD imidazole
  • Example 61 2-(4-Fluorophenyl -l-(2-(l-(S -phenylethyl)amino-4-pyrimidyl)-4-(4- acetyl)piperidine-l-yl imidazole
  • Agents of the Invention as defined above, e.g., of formula I, particularly as exemplified, in free or pharmaceuticaUy acceptable acid addition salt form, exhibit pharmacological activity and are useful as pharmaceuticals, e.g. for therapy, in the treatment of diseases and conditions as hereinafter set forth.
  • Agents of the Invention possess p38 MAP kinase (Mitogen Activated Protein Kinase) inhibiting activity.
  • the Agents of the Invention act to inhibit production of inflammatory cytokines, such as TNF- ⁇ and IL-1, and also to potentiaUy block the effects of these cytokines on their target ceUs.
  • the substrate (GST-ATF-2; a fusion protein comprising amino acids 1-109 of ATF-2 and the GST protein obtained by expression in E. coU) is coated onto the weUs of microtiter plates (50 ⁇ l/weU; 1 ⁇ g/ml in PBS/0.02% Na azide) overnight at 4 °C.
  • the foUowing day the microtiter plates are washed four times with PBS/0.5% Tween 20/0.02% Na azide and are blocked with PBS/2% BSA 0.02% Na Azide for 1 h at 37 °C. Plates are washed again 4 times with PBS/0.5% Tween 20/0.02% Na azide.
  • the kinase cascade reaction is then started by adding the foUowing reactants in 10 ⁇ l aUquots to a final reaction volume of 50 ⁇ l.
  • Agents of the Invention titrated from 10 to 0.001 ⁇ M in 10-fold dUutions or solvent (DMSO) or H 2 O.
  • His-p38 MAP kinase (10 ng/weU; Novartis - a fusion protein comprising fuU length murine p38 MAP kinase and a His tag, obtained by expression in E. coU)
  • Biotin labeUed goat-anti-rabbit IgG (50 ⁇ l/weU; 1/3000 final dUution in PBS/2% BSA/0.02% Na Azide; Sigma #B-9642) for 90 min at RT.
  • Substrate 100 ⁇ l/weU; Sigma 104 Phosphatase substrate tablets, 5 mg/tablet; #104-105; 1 mg/ml in substrate buffer, Diethanolamine (97 ml/1; Merck #803116) + MgCl 2 .6H 2 0 (100 mg/1; Merck #5833) + Na Azide (0.2 g/1) + HC1 1M to pH 9.8) 30 min at RT.
  • step 12 and 3 the microtiter plates are washed four times with PBS/0.5% Tween 20/0.02% Na azide.
  • step 4 the plates are read in a Bio-Rad microplate reader in a dual wavelength mode (measurement filter 405 nm and reference filter 490 ran). The bachground value (without ATP) is subtracted and IC50 values are calculated using the Origin computer program (4 parameter logistic function).
  • Agents of the Invention typicaUy have IC 50 S for p38 MAP kinase inhibition in the range from about 100 nM to about 10 nM or less when tested in the above assay.
  • the compounds of Examples 9, 14, 15,18-23, 30-33, 35, 49, 51, 52 and 55-57 have IC 50 s for ⁇ 38 MAP kinase inhibition in the range from about 1 nM to about 10 nM when tested in the above assay.
  • hPBMCs Human peripheral blood mononuclear cells
  • TNF- ⁇ in the supernatant is measured using a commercial ELJSA (Innotest hTNFa, available from Innogenetics N.V., Zwijnaarde, Belgium).
  • Agents of the Invention are tested at concentrations of from 0 to 10 mM.
  • Exemplified Agents of the Invention typicaUy suppress TNF release in this assay with an IC 50 of from about 500 nM to about 10 nM or less when tested in this assay.
  • the compounds of Examples 4, 8, 9, 19, 20, 23, 31-33, 35 and 49-57, 59 and 60 have IC 50 s in the range from about 10 nM to about 1 nM.
  • LPS Upopolysaccharide
  • TNF- ⁇ soluble tumour necrosis factor
  • LPS (20 mg/kg) is injected i.v. into OF1 mice (female, 8 week old). One (1) hour later blood is withdrawn from the animals and TNF levels are analysed in the plasma by an ELIS A method using an antibody to TNF- ⁇ . Using 20 mg/kg of LPS levels of up to 15 ng of TNF- ⁇ / ml plasma are usuaUy induced. Compounds to be evaluated are given either oraUy or s.c. 1 to 4 hours prior to the LPS injection. Inhibition of LPS-induced TNF-release is taken as the readout.
  • Agents of the Invention typicaUy inhibit TNF production to the extent of up to about 50% or more in the above assay when administered at 10 mg/kg p.o.
  • Agents of the Invention are potent inhibitors of TNF- ⁇ release. Accordingly, the Novel Compounds have pharmaceutical utility as foUows:
  • Agents of the Invention are useful for the prophylaxis and treatment of diseases or pathological conditions mediated by cytokines such as TNF ⁇ and IL-1, e.g., inflammatory conditions, autoimmune diseases, severe infections, and organ or tissue transplant rejection, e.g. for the treatment of recipients of heart, lung, combined heart-lung, Uver, kidney, pancreatic, skin or corneal transplants and for the prevention of graft-versus-host disease, such as foUowing bone marrow transplants.
  • cytokines such as TNF ⁇ and IL-1
  • inflammatory conditions e.g., inflammatory conditions, autoimmune diseases, severe infections, and organ or tissue transplant rejection
  • graft-versus-host disease such as foUowing bone marrow transplants.
  • Agents of the Invention are particularly useful for the treatment, prevention, or ameUoration of autoimmune disease and of inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases.
  • autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases.
  • Specific auto-immune diseases for which Agents of the Invention may be employed include autoimmune haematological disorders (including e.g.
  • hemolytic anaemia aplastic anaemia, pure red ceU anaemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven- Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g.
  • ulcerative coUtis and Crohn's disease endocrine ophthalmopathy
  • Graves disease sarcoidosis, multiple sclerosis, primary bittary cirrhosis, juvenUe diabetes (diabetes meUitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy).
  • Agents of the Invention are also useful for the treatment, prevention, or ameUoration of asthma, bronchitis, pneumoconiosis, pulmonary emphysema, and other obstructive or inflammatory diseases of the airways.
  • Agents of the Invention are useful for treating undesirable acute and hyperacute inflammatory reactions which are mediated by TNF, especiaUy by TNFa, e.g., acute infections, for example septic shock (e.g., endotoxic shock and adult respiratory distress syndrome), meningitis, pneumonia; and severe burns; and for the treatment of cachexia or wasting syndrome associated with morbid TNF release, consequent to infection, cancer, or organ dysfunction, especiaUy AIDS -related cachexia, e.g., associated with or consequential to HTV infection.
  • acute infections for example septic shock (e.g., endotoxic shock and adult respiratory distress syndrome), meningitis, pneumonia; and severe burns; and for the treatment of cachexia or wasting syndrome associated with morbid TNF release, consequent to infection, cancer, or organ dysfunction, especiaUy AIDS -related cachexia, e.g., associated with or consequential to HTV infection.
  • septic shock e.g., endotoxic shock
  • Agents of the Invention are particularly useful for treating diseases of bone metaboUsm including osteoarthritis, osteoporosis and other inflammatory arthritides.
  • the appropriate dosage wiU may vary depending, for example, on the particular Agent of the Invention employed, the subject to be treated, the mode of administration and the nature and severity of the condition being treated.
  • daUy dosages of from about 1 to about lOmg/kg/day p.o..
  • an indicated daUy dosage is in the range of from about 50 to about 750mg of Novel Compound administered oraUy once or, more suitably, in divided dosages two to four times/day.
  • the Novel Compounds may be administered by any conventional route, e.g. oraUy, for example in the form of solutions for drinking, tablets or capsules or parenteraUy, for example in the form of injectable solutions or suspensions.
  • NormaUy for systemic administration oral dosage forms are preferred, although for some indications the Novel Compounds may also be administered topicaUy or dermaUy, e.g. in the form of a dermal cream or gel or like preparation or, for the purposes of appUcation to the eye, in the form of an ocular cream, gel or eye-drop preparation; or may be administered by inhalation, e.g., for treating asthma.
  • Suitable unit dosage forms for oral administration comprise e.g. from 25 to 250mg Novel Compound per unit dosage.
  • the present invention also provides in a further series of embodiments:
  • a method of inhibiting production of soluble TNF, especiaUy TNF ⁇ , or of reducing inflammation in a subject i.e., a mammal, especiaUy a human
  • a subject i.e., a mammal, especiaUy a human
  • which method comprises administering to said subject an effective amount of an Agent of the Invention, or a method of treating any of the above mentioned conditions, particularly a method of treating an inflammatory or autoimmune disease or condition, e.g. rheumatoid arthritis, or aUeviating one or more symptoms of any of the above mentioned conditions.
  • An Agent of the Invention for use as a pharmaceutical, e.g. for use as an immunosuppressant or antiinflammatory agent or for use in the prevention, ameUoration or treatment of any disease or condition as described above, e.g., an autoimmune or inflammatory disease or condition.
  • a pharmaceutical composition comprising an Agent of the Invention in association with a pharmaceuticaUy acceptable dUuent or carrier, e.g., for use as an immunosuppressant or anti- inflammatory agent or for use in the prevention, ameUoration or treatment of any disease or condition as described above, e.g., an autoimmune or inflammatory disease or condition.
  • a pharmaceuticaUy acceptable dUuent or carrier e.g., for use as an immunosuppressant or anti- inflammatory agent or for use in the prevention, ameUoration or treatment of any disease or condition as described above, e.g., an autoimmune or inflammatory disease or condition.

Abstract

L'invention concerne des composés correspondant à la formule (I) dans laquelle les symboles possèdent les notations données dans la description. Ces composés constituent des inhibiteurs de la protéine kinase p38 activée par les mitogènes et sont utiles dans le domaine pharmaceutique pour traiter les maladies induites par le facteur de nécrose tumorale α et IL-1, telles que la polyarthrite rhumatoïde, ainsi que des maladies du métabolisme osseux, par exemple l'ostéoporose.
PCT/EP2000/003290 1999-04-14 2000-04-12 Azoles substitues WO2000063204A2 (fr)

Priority Applications (17)

Application Number Priority Date Filing Date Title
EP00922630A EP1224180B1 (fr) 1999-04-14 2000-04-12 Azoles substitues
AU42953/00A AU4295300A (en) 1999-04-14 2000-04-12 Substituted azoles
DE60003709T DE60003709T2 (de) 1999-04-14 2000-04-12 Substituierte azole
BR0010598-8A BR0010598A (pt) 1999-04-14 2000-04-12 Azoles substituìdos
SK1456-2001A SK14562001A3 (sk) 1999-04-14 2000-04-12 Substituované azoly, spôsob ich prípravy, farmaceutická kompozícia s ich obsahom a ich použitie
PL00364789A PL364789A1 (en) 1999-04-14 2000-04-12 Substituted azoles
JP2000612294A JP2003503311A (ja) 1999-04-14 2000-04-12 置換アゾール類
KR1020017013086A KR20010108504A (ko) 1999-04-14 2000-04-12 치환 아졸
HU0302747A HUP0302747A2 (hu) 1999-04-14 2000-04-12 Szubsztituált azolok, eljárás az előállításukra és ezeket tartalmazó gyógyszerkészítmények
MXPA01010434A MXPA01010434A (es) 1999-04-14 2000-04-12 Azoles sustituidos.
IL14583600A IL145836A0 (en) 1999-04-14 2000-04-12 Substituted azoles
AT00922630T ATE244236T1 (de) 1999-04-14 2000-04-12 Substituierte azole
DK00922630T DK1224180T3 (da) 1999-04-14 2000-04-12 Substituerede azoler
SI200030185T SI1224180T1 (en) 1999-04-14 2000-04-12 Substituted azoles
CA002370417A CA2370417A1 (fr) 1999-04-14 2000-04-12 Azoles substitues
US09/975,913 US6579874B2 (en) 1999-04-14 2001-10-12 Substituted azoles
NO20014987A NO20014987L (no) 1999-04-14 2001-10-12 Substituerte azoler

Applications Claiming Priority (4)

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GBGB9908531.8A GB9908531D0 (en) 1999-04-14 1999-04-14 Organic compounds
GB9908532.6 1999-04-14
GBGB9908532.6A GB9908532D0 (en) 1999-04-14 1999-04-14 Organic compounds
GB9908531.8 1999-04-14

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EP (1) EP1224180B1 (fr)
JP (1) JP2003503311A (fr)
KR (1) KR20010108504A (fr)
CN (1) CN1378544A (fr)
AR (1) AR023465A1 (fr)
AT (1) ATE244236T1 (fr)
AU (1) AU4295300A (fr)
BR (1) BR0010598A (fr)
CA (1) CA2370417A1 (fr)
CO (1) CO5170501A1 (fr)
CZ (1) CZ20013696A3 (fr)
DE (1) DE60003709T2 (fr)
DK (1) DK1224180T3 (fr)
ES (1) ES2202114T3 (fr)
HU (1) HUP0302747A2 (fr)
IL (1) IL145836A0 (fr)
MX (1) MXPA01010434A (fr)
NO (1) NO20014987L (fr)
PE (1) PE20010031A1 (fr)
PL (1) PL364789A1 (fr)
PT (1) PT1224180E (fr)
SK (1) SK14562001A3 (fr)
TR (1) TR200102967T2 (fr)
WO (1) WO2000063204A2 (fr)

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PL364789A1 (en) 2004-12-13
IL145836A0 (en) 2002-07-25
PE20010031A1 (es) 2001-02-23
PT1224180E (pt) 2003-11-28
BR0010598A (pt) 2002-02-05
HUP0302747A2 (hu) 2003-12-29
EP1224180A2 (fr) 2002-07-24
JP2003503311A (ja) 2003-01-28
NO20014987L (no) 2001-12-14
US6579874B2 (en) 2003-06-17
CA2370417A1 (fr) 2000-10-26
CN1378544A (zh) 2002-11-06
CO5170501A1 (es) 2002-06-27
WO2000063204A3 (fr) 2002-05-23
EP1224180B1 (fr) 2003-07-02
DK1224180T3 (da) 2003-10-20
TR200102967T2 (tr) 2002-01-21
KR20010108504A (ko) 2001-12-07
MXPA01010434A (es) 2002-03-27
AR023465A1 (es) 2002-09-04
US20020049220A1 (en) 2002-04-25
DE60003709D1 (de) 2003-08-07
NO20014987D0 (no) 2001-10-12
ES2202114T3 (es) 2004-04-01
SK14562001A3 (sk) 2002-03-05
DE60003709T2 (de) 2004-12-23
CZ20013696A3 (cs) 2002-02-13
AU4295300A (en) 2000-11-02
ATE244236T1 (de) 2003-07-15

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